NK cells are critical components of our immune system functioning, in part, to recognize and then eradicate virally infected or tumorigenic cells without previous sensitization. One of the best-characterized activating receptors expressed on NK cells is the NKG2D receptor, which is capable of transmitting co-stimulatory signals by subsets of T cells. Viruses and tumors have evolved strategies to evade NKG2D-mediated immune recognition thus highlighting the importance of this receptor in immunity. This review will focus on the structure of NKG2D and its interaction with its diverse array of ligands, as well as highlighting current knowledge regarding NKG2D signal transduction and biological mechanisms that govern its cell surface expression. The impact that NKG2D has in disease pathologies is also assessed.